Blood vessels are organs essential for the survival and maintenance of normal functions of all types of cells in the human body. Particularly, vascular endothelial cells that are found in the innermost part of blood vessels are present as a single layer and form a cellular barrier that controls the leakage of blood proteins, fluids and electrolytes into the surrounding tissues. The gaps between vascular endothelial cells are very narrow in normal blood vessels, and thus the permeability of the blood vessels is low. However, when blood vessels are infiltrated by inflammatory cells or damaged to cause hypoxia, the secretion of various cytokines and growth factors such as vascular endothelial growth factor (VEGF) significantly increases. Particularly, VEGF stimulates the proliferation, survival and migration of vascular endothelial cells to promote angiogenesis, and at the same time, significantly increases vascular permeability by increasing the gap between vascular endothelial cells. Thus, blood vessels formed by the over-expression of VEGF are characterized in that the leakage of fluids into the surrounding tissues increases.
An excessive increase in vascular permeability causes various diseases. Particularly, an excessive increase in vascular permeability in retina or choroid stimulates hemorrhage and macular edema, and thus is the most common cause of fatal visual loss. Typical diseases that are caused by this pathogenic mechanism include diabetic retinopathy (DR), diabetic macular edema (DME), age-related macular degeneration (AMD), choroidal neovascularization, retinopathy of prematurity (ROP), and the like. Macular edema occurs in 2-6% of patients with mild diabetic retinopathy, 20-63% of patients with moderate diabetic retinopathy, and 70% or more of patients with severe diabetic retinopathy. Once macular edema occurs, the loss of vision appears in about 50% of the patients. In order to prevent serious visual impairment or loss from being caused by diabetes, methods of treating and inhibiting macular edema by reducing capillary leakage have been attempted, and it was reported that, when the activity of VEGF that increases vascular permeability is inhibited, the effect of inhibiting angioedema appears. Known methods for inhibiting the activity of VEGF include a method of reducing vascular permeability by inhibiting the activity of VEGF receptor using antibodies (Bevacizumab, Ranibizumab, etc.) that bind directly to VEGF, a method of inhibiting macular edema using PKC (protein kinase C) inhibitors (ruboxistaurin, etc.) that induce the endocytosis of vascular endothelial tight junction molecules, and a method of simultaneously inhibiting VEGF receptors and Src (soluble tyrosine kinase) that is involved in the signaling pathways of VEGF and VEGF receptors to increase retinal vascular permeability. However, studies on the regulation of angiogenesis and vascular permeability, conducted to date, have mostly been limited to VEGF or VEGF receptors, and have mostly been focused on the development of inhibitors against the genes. Thus, studies on the regulation of angiogenesis and vascular permeability are still insufficient.